The overall objective of the research is to determine in animal model systems the mode of action of the biguanide phenformin on diabetes-induced hepatic gluconeogenesis and the physiological factors that regulate this action. The animal model systems used are diabetic rats and diabetic guinea pigs. These animals serve as donors for isolated perfused liver experiments. Such experiments constitute the central methodology employed in closely integrated projects. These projects include: The determination of the influence of diabetes on phenformin metabolism. The determination of the specific enzyme-catalyzed reaction sites of gluconeogenesis in diabetic liver that are acted on (directly or indirectly) by phenformin. The determination of the influence of glucagon and insulin on the above hepatic action of phenformin. The results of these studies will provide significant new information on the action of hypoglycemic biguanides in diabetic animal model systems as well as provide the information that is needed to effectively use and study these drugs in diabetic humans.